The purpose of this study was to examine the function and regulation of natural killer cells in vitro and in vivo in patients with multiple sclerosis. Of 12 patients who received 5 X 10(6) international units of human alpha interferon, 9 demonstrated an increase in natural killer cell activity within 48 hours as defined by the lysis of 51Cr-labeled K-562 cells. The activity was normal before treatment, unlike that of tumor-bearing patients, and reached baseline levels within one week despite continuous interferon administration over the next six months. The same patients given a placebo preparation failed to show this enhanced natural killer cell activity. We also studied K-562 killing in 36 other patients and age- and sex-matched control subjects and were unable to demonstrate any differences between the two groups or any correlation of natural killer cell function with disease activity. The in vitro augmentation of natural killer cell activity by purified measles virions, which is associated with the release of interferon, and by the isolated glycoproteins of measles virus, which activates natural killer cells without the extracellular release of interferon, was similar in both patients and control subjects. Further, the proportion of cells defined by the monoclonal antibody HNK-1, which defines both natural killer cells and a small subset of cytotoxic T lymphocytes, was normal. In patients with multiple sclerosis, the normality of natural killer cell function, as defined by these several interrelated assays, speaks against a defect in this nonspecific antiviral defense mechanism in the pathogenesis of the disease.